One-pot three-component catalytic enantioselective synthesis of homoallylboronates

Article abstract of DOI:10.1002/anie.201105458

No longer a simple bor(ation): The title reaction between bis(pinacolato)diboron, enals, and 2-(triphenylphosphoranylidene)acetates employing bench-stable copper salts and a simple chiral amine co-catalyst is presented (see scheme). The reaction proceeds

Full text of DOI:10.1002/anie.201105458

Communications
DOI: 10.1002/anie.201105458
Synthetic Methods
One-Pot Three-Component Catalytic Enantioselective Synthesis of
Homoallylboronates**
Ismail Ibrahem,* Palle Breistein, and Armando Cꢀrdova*
The synthesis of enantioenriched a-chiral organoboron com-
addition product B after 2 hours (50% conv., 45% yield)
pounds has received significant attention in chemical syn-
[Eq. (1)].
ꢀ
ꢀ
ꢀ
thesis because the C B bond can be converted into C O, C
[1]
ꢀ
N, and C C bonds in a stereospecific fashion. Thus, the
design of efficient catalytic protocols for asymmetric synthesis
of boron-containing compounds is of utmost interest for
organic synthesis.[2,3] In this context, homoallyl- and allylbor-
onates are highly useful since additional derivatization using
the alkene moiety as well as the boron group gives rapid
access to multifunctional chiral compounds. They can also be
used as chiral nucleophiles for additions to either aldehydes
and ketones, or imines to give the corresponding alcohols or
amines, respectively.[1b1 The metal-mediated enantioselective
hydroboration of alkenes is an important method for the
preparation of chiral organoboron compounds.[3] With respect
to the synthesis of enantioenriched homoallylboronates, Ito
and co-workers disclosed an elegant protocol for the synthesis
of enantioenriched cyclic homoallylboronates by copper-
catalyzed regioselective asymmetric monoborylation of 1,3-
dienes using bis(pinacolato) diboron (B2pin2; 1).[4] B2pin2 (1)
has also been successfully employed as the boryl reagent in
chiral copper phosphine complexes[5] or bidentate N-hetro-
cyclic carbene copper complexes to catalyze[6] enantioselec-
tive conjugate additions to a,b-unsaturated carbonyl com-
pounds, alkenes, alkynes, and dienes. However, the regio-
selective and enantioselective 1,6-addition of 1 to 2,4-
dienaote esters such as A to give the corresponding homo-
allylboranes 4 has, to the best of our knowledge, not been
disclosed (see Eq. (1) for structures).[7] This reaction is
challenging and is more likely to render the 1,4-addition
product B or a mixture of both compounds. In fact, perform-
ing the copper-catalyzed addition of 1 to phenyl-2,4-dienaote
A using PPh3 (7a) as the ligand gave exclusively the 1,4-
Multicomponent reactions that involve the formation of
ꢀ
multiple C C and carbon–heteroatom bonds in a highly
chemo- and stereoselective fashion in one pot is an important
research field within chemical synthesis. In particular, the
development of catalytic asymmetric multicomponent reac-
tions is a difficult task.[8] Based on the importance of
discovering new enantioselective multicomponent reactions,
we envisioned an alternative route to the enantioenriched
homoallylboronates 4 by a one-pot catalytic asymmetric
borane conjugate addition/Wittig reaction sequence using 1,
the a,b-unsaturated aldehydes 2, and 2-(triphenylphosphor-
anylidene)acetate esters 3 [Eq. (2)].
The key to success for the one-pot synthesis of the
homoallylboranes 4 is the ability to control and develop the
challenging catalytic enantioselective b-boration step of the
enal component 2 to give the corresponding enantioenriched
b-boryl aldehyde intermediate 5 prior to the Wittig step
(Scheme 1). However, this type of transformation can be
plagued by 1,2-addition to give the product 5ꢀ as well.[8] In this
context, our previous research has shown that it is possible to
achieve highly selective conjugate additions of silyl[10a] and
carbon nucleophiles (organozinc reagents)[10b] to enals 2 by
combining transition-metal and aminocatalysts.[10–13] Thus,
retrocatalytic analysis suggests that the ability of a chiral
amine to lower the LUMO of the enal component 2 by
iminium activation[14] in combination with copper-catalyzed
conjugate addition[15] of the Bpin to this intermediate may
favor enantioselective 1,4-addition over 1,2-addition to pre-
dominantly give the intermediate 5 (Scheme 1). Its subse-
quent Wittig reaction with 3 would give the enantioenriched
homoallylicboronate product 4.
[*] Prof. Dr. I. Ibrahem, P. Breistein, Prof. Dr. A. Cꢀrdova
Department of Natural Sciences, Engineering and Mathematics
Mid Sweden University, SE-851 70 Sundsvall (Sweden)
E-mail: ismail.ibrahem@miun.se
armando.cordova@miun.se
Prof. Dr. A. Cꢀrdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University (Sweden)
E-mail: acordova@organ.su.se
Prof. Dr. A. Cꢀrdova
The Berzelii Center EXSELENT, Stockholm University (Sweden)
[**] Financial support was provided by the Mid Sweden University and
the European Union. We are grateful to Hꢁkan Norberg for help in
setting up the laboratory.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105458.
12036
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12036 –12041

With these results in hand, we decided
to probe the scope of the catalytic one-pot
three-component enantioselective reaction
using Cu(OTf)2 as the metal catalyst, 6a as
the chiral amine, and 7a as the phosphine
additive in diethyl ether at 228C
(Scheme 2). The three-component reac-
tions were efficient and proceeded with
excellent 1,4-selectivity in the b-boration
step and the corresponding homoallylbor-
onates 4a–4j were assembled in an asym-
metric fashion in good yields and high
enantiomeric ratios through the conjugate
boron addition/Wittig sequence. The reac-
Scheme 1. Proposed reaction sequence. L=ligand.
Herein we disclose the unprecedented one-pot three-
component enantioselective catalytic reaction between 1, a,b-
unsaturated aldehydes, and (triphenylphosphoranylidene)-
acetate esters, thereby giving the corresponding homoallyl-
borane products in good yields and up to 97.5:2.5 e.r. This
method employs readily available transition metals and chiral
amines as co-catalysts.
We began our investigation by studying the catalytic one-
pot three-component reaction between 1, cinnamic aldehyde
(2a), and the phosphorane 3a using different copper salts,
chiral amines (6), and phosphine ligands (7). Key results are
shown in Table 1. We found that performing the one-pot
reaction without the use of a chiral amine catalyst (6) gave
low 1,4-selectivity in the initial b boration of the enal 2a,
which gave both racemic aldehyde 5a and 5a’ in a 67:33 ratio
as determined by 1H NMR analysis of the crude reaction
mixture prior to the addition of the Wittig reagent 7a
(entry 1). The reaction without the copper(II) triflate (Cu-
(OTf)2) catalyst but in the presence of the chiral amine 6a
gave a small amount (< 2% conv.) of 5a (entry 2). To our
delight, the homoallylicboronate 4a was assembled in an
asymmetric fashion when commercially available chiral
amines 6a–6d were used as catalysts in combination with
Cu(OTf)2 (5 mol%) as the transition-metal co-catalyst and
Ar3P (7) as the ligand in diethyl ether at 228C. MeOH
(3 equiv) was added to maintain the copper-catalyzed activa-
tion of the borane reagent 1. It is noteworthy that we were
able to isolate the aldehyde 5a intermediate (the e.r. could
only be determined after conversion of 5a into 4a). However,
it was hard to purify since it decomposes (e.g., elimination)
during silica gel column chromatography to give the starting
enal 2a, which has the same Rf value. The addition of an
organic acid additive leads to significant improvement of both
the 1,4- and enantioselectivity of the asymmetric b-boration
step (entries 7 and 9). In fact, only b boration occurred when
2-fluorobenzoic acid was used as the additive. Thus, the protic
acid additive accelerated the catalytic cycle of the iminium
formation and as a consequence the chemoselectivity was
directed towards 1,4-addition. Of the investigated chiral
amines 6, the highest reactivity and enantioselectivity of the
Scheme 2. [a] 35 min. [b] 2h (3 equiv), 60 min. [c] 48C, 45 min.
tion tolerated enals with both aryl and aliphatic substituents
at their b position. Moreover, cinnamic enals 2 with an
electron-withdrawing group at the para, ortho, or meta posi-
tion exhibit higher reactivity in the b-boration step
(Scheme 1). For example, the b boration of enals 2d–2g and
2j was completed within 35 minutes as determined by
1H NMR analysis. The subsequent addition of the Wittig
reagents 3 gave the corresponding homoallylboranes 4d–4g
and 4j with 96.5:3.5–97:5:2.5 e.r. after 2 hours. The yields
were in the range of 60–67% because the intermediates
decomposed through elimination during the Wittig step to
give the enals 2. Thus, a small amount of the corresponding
diene A was also formed. We also investigated the reactions
with enals 2 wherein either R was heterocyclic or 2 was
b substituted. However, the reactions were slower and the
corresponding products 4 were formed with lower e.r. values
ꢀ
B C bond-forming step was achieved when the chiral amine
6a[16] was employed as the catalyst and the corresponding
homoallylicboronate product 4a was isolated in 65% yield
with 97.5:2.5 e.r. (entry 7).
Angew. Chem. Int. Ed. 2011, 50, 12036 –12041
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Communications
Table 1: Initial examination of catalytic one-pot three-component synthesis of 4a[a]
Entry[a]
Amine
7
Cu salt
t [h]
Conv. [%][b]
e.r.[c]
1[d]
2
3
4
5
6
7
8
–
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
7a
7a
7a
7b
Cu(OTf)2
–
CuCl
CuBr
CuI
CuOAc
Cu(OTf)2
CuOCl2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
1
7
4
4
4
4
1
4
1
4
4
4
4
1
2
1
7
60
<2
<2
<2
<2
<2
98
<2
98
70
24
70
30
80
95
85
20
50:50
n.d.
n.d.
n.d.
n.d.
n.d.
97.5:2.5
n.d.
69:31
90:10
63:37
85:15
80:20
55:45
72:28
53:47
n.d.
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
9[e]
10
11
12
13
14
15
16
17
[a] Under N2 atmosphere. See the Supporting Information for details of the reaction conditions. [b] Conversion into aldehyde 5a as determined from
the 1H NMR spectra of the crude reaction mixture. [c] Determined by HPLC analysis of 4a on a chiral stationary phase. [d] Without the addition of the
chiral amine catalyst 6a, the 1,4-/1,2-addition ratio was 67:33, as determined by 1H NMR analysis of the crude reaction mixture prior to the Wittig step.
[e] Without the addition of 2-fluorobenzoic acid, the 1,4-/1,2-addition ratio was 75:25, as determined by 1H NMR analysis of the crude reaction mixture
prior to the Wittig step. n.d.=not determined, TES=triethylsilyl, TMS=trimethylsilyl.
(60:40–65:35). To establish the absolute configuration of the
homoallylicboronates 4 and show the synthetic utility of our
asymmetric multicomponent reaction, we investigated a one-
pot transformation for the assembly of the valuable homo-
allylic alcohol 8a (Scheme 3).[17,18] The one-pot reaction was
successful and we were able to isolate the corresponding
homoallylic alcohol 8a in 60% yield. Comparison with the
literature revealed that the stereochemistry at C5 was S
boronates 4 is S (R = aryl). We also broadened the scope of
the strategy by synthesizing homoallylic amine 8b in 65%
yield.[19]
The presence of chiral iminium intermediates derived
from the reaction of the catalyst 6a and enal 2a in the b-
boration step of our one-pot three-component reaction was
confirmed by 1H NMR and HRMS analysis of the crude
reaction mixture. In addition, subjecting the cinnamic ester 9a
to the same reactions conditions that were used for the
synthesis of homoallylboronate 4a gave the corresponding
racemic b-borylated product 10a [Eq. (3)]. Furthermore,
20
(½aꢁD ¼ꢀ15.30 degcm3 gꢀ1 dmꢀ1 (c = 1.0 gcmꢀ3, EtOH); Lit.
20
(R)-8:
½aꢁD ¼ + 10.40 degcm3 gꢀ1 dmꢀ1
(c = 1.1 gcmꢀ3,
EtOH).[17] Thus, the absolute configuration of the homoallyl-
12038 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12036 –12041

Scheme 3. One-pot catalytic enantioselective synthesis of homoallylic
alcohol 8a and homoallylic amine 8b.
Scheme 4. Proposed reaction mechanism.
ꢀ
quent C B formation at the Re face of the iminium inter-
mediade E gives F. Hydrolysis and addition of MeOH
regenerates the chiral amine catalyst 6, thus leading to
II
ꢀ
ꢀ
formation of a reactive MeO Cu L species and the b-
borylaldehyde intermediate 5. Next, the in situ Wittig reac-
tion with 3 gives the final homoallylboronate product 4.
In summary, we have developed an efficient, novel one-
pot three-component enantioseelctive reaction between a
diboron reagent, a,b-unsaturated aldehydes, and 2-(tri-
phenylphosphoranylidene)acetate esters. The asymmetric
multicomponent reaction proceeds through a b boration/
Wittig sequence to give the corresponding homoallylboro-
nates with high enantiomeric ratios using simple bench-stable
chiral amines and copper catalysts. In addition, the study
shows that it is possible to merge the catalytic cycles of
transition-metal-catalyzed nucleophilic activation of diboron
reagents with amine-catalyzed iminium activation of enals to
achieve a highly 1,4- and enantioselective b boration of enals.
The one-pot expansion of the co-catalytic three-component
reaction to the asymmetric synthesis of homoallylic alcohols
was also disclosed. Further development of this type of one-
pot multicomponent co-catalytic asymmetric reaction and its
application in total synthesis is ongoing in our laboratories.
subjecting a,b-unsaturated ketone 11a, which is known to not
form iminium intermediates with the bulky amino catalyst
6a,[16] to the reaction conditions used for the b boration of
enals 2 gave nearly racemic b-borolyated ketone 12a
[Eq. (4)]. These results indicate that iminium activation is
necessary to make the one-pot three-component reaction
enantioselective.
Based on the absolute configuration of the products 4, the
above experimental results, and our previous DFT calcula-
tions,[10] we propose the reaction mechanism depicted in
II
ꢀ
ꢀ
Scheme 4. The in situ generated L Cu Bpin C species
approaches the less sterically hindered Si face (R = aryl) of
the b-carbon atom of the imiunium intermediate D. Subse-
Received: August 2, 2011
Revised: September 7, 2011
Published online: October 18, 2011
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www.angewandte.org 12039

Communications
Bunz, V. Lillo, E. Fern¼ndez, P. J. Guiry, Org. Biomol. Chem.
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[7] For transition-metal-catalyzed asymmetric 1,6-addition to
Keywords: asymmetric catalysis · boron · conjugate additions ·
multicomponent reactions · Wittig reactions
.
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